Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample.
Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample.
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蛋氨酸代谢和 X-ALD 表型生成的遗传变异：新研究样本的结果。
DOI：
10.1007/s00415-009-5114-6
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发表时间：
2009
影响因子：
6
通讯作者：
Linnebank,Michael
中科院分区：
文献类型：
--
作者：
Semmler,Alexander;Bao,Xinhua;Cao,Guangna;Köhler,Wolfgang;Weller,Michael;Aubourg,Patrick;Linnebank,Michael
X连锁肾上腺脑白质营养不良(X-ALD)是最常见的遗传性脑白质营养不良。然而，到目前为止，还没有建立起基因与表型的相关性。未确定的修饰基因或其他辅助因素被怀疑调节表型和预后。我们最近描述了蛋氨酸代谢的多态可能是X-ALD的疾病修饰物。为了重新检验这些发现，我们分析了来自不同人群(法国、德国、美国、中国)的172个新的X-ALD患者的dna样本，通过对8个蛋氨酸代谢的遗传变异进行基因分型，包括dhfr c.594+59del19BP、cbs c.844_855ins68、mtr c.2756A>；G、mtfr c.677C>；T和c.1298A>；C、mtrr c.60A>；G、RFc1 c.80G>；A和Tc2 c.776C>；G。成年期起病伴局灶性脑脱髓鞘(ACALD；n=38)，成年期起病无脑脱髓鞘(AMN；n=652)。用皮尔逊双侧χ2进行单因素分析，发现TC 2 c.776C&Gt；G等位基因与X-ALD表型相关(χ2=6.1P=0.048)。中枢神经系统脱髓鞘患者Tc2c.776C>；G的GG基因型频率高于无脱髓鞘患者(χ2=44.42，P=0.036)。慢性萎缩性肝病患者的GG基因频率也高于AMN患者(χ2=44.7，P=0.031)。在本研究样本中，其他多态没有显示出任何显著的关联。虽然蛋氨酸代谢的其他多态的影响尚未得到证实，但本研究支持先前的观察结果，即Tc2基因对X-ALD表型的产生有贡献。
X-linked adrenoleukodystrophy (X-ALD) is the most common inherited leukodystrophy. Nevertheless, no genotype–phenotype correlation has been established so far. Unidentified modifier genes or other cofactors are suspected to modulate phenotype and prognosis. We recently described polymorphisms of methionine metabolism as possible disease modifiers in X-ALD. To retest these findings, we analyzed 172 new DNA samples of X-ALD patients from different populations (France, Germany, USA, China) by genotyping eight genetic variants of methionine metabolism, including DHFR c.594+59del19bp, CBS c.844_855ins68, MTR c.2756A>G, MTHFR c.677C>T and c.1298A>C, MTRR c.60A>G, RFC1 c.80G>A, and Tc2 c.776C>G. We compared three X-ALD phenotypes: childhood-onset cerebral demyelinating inflammatory type (CCALD;n= 82), adulthood onset with focal cerebral demyelination (ACALD;n= 38), and adulthood onset without cerebral demyelination (AMN;n= 52). The association of genotypes and phenotypes was analyzed with univariate two-sided Pearson’sχ2. In the comparison between AMN and CCALD, the G allele of Tc2 c.776C>G was associated with X-ALD phenotypes (χ2= 6.1;P= 0.048). The prevalence of the GG genotype of Tc2 c.776C>G was higher in patients with CNS demyelination compared to those without CNS demyelination (χ2= 4.42;P= 0.036). The GG genotype was also more frequent in CCALD compared to AMN (χ2= 4.7;P= 0.031). The other polymorphisms did not show any significant associations in this study sample. Whereas the influence of other polymorphisms of methionine metabolism was not confirmed, the present study supports the previously made observation that the Tc2 genotype contributes to X-ALD phenotype generation.